After a traumatic injury, hemorrhage is responsible for over 35% of pre-hospital deaths and over 40% of deaths within the first 24 hours (Kauvar, D. S., Lefering, R., and Wade, C. E. (2006), Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations, J Trauma 60, 53-11), second only to the rates of death due to severe central nervous system injury. A cascade of medical problems (e.g., hemorrhage, impaired resuscitation, shock, inflammation and coagulopathy) may be life threatening, can begin with severe hemorrhage, and may occur simultaneously. The severity of each such problem is commonly associated with the extent of overall blood loss. Low blood pressure due to blood loss indicates immediate complications, including the incidence of multiple organ failure and life-threatening infections. See Heckbert, S. R., Vedder, N. B., Hoffman, W., Winn, R. K., Hudson, L. D., Jurkovich, G. J., Copass, M. K., Harlan, J. M., Rice, C. L., and Maier, R. V. (1998), Outcome after hemorrhagic shock in trauma patients. J Trauma 45, 545-549. See also, Franklin, G. A., Boaz, P. W., Spain, D. A., Lukan, J. K., Carrillo, E. H., and Richardson, J. D. (2000) Prehospital hypotension as a valid indicator of trauma team activation. J Trauma 48, 1034-1037; discussion 1037-1039.
Early trauma care focuses on minimizing hemorrhage and restoring circulation effectively.
Mitigation of battlefield injury and hemorrhage is a high priority of U.S. military trauma surgeons and researchers. There is no debate about the importance of hemorrhage control as a first-line measure by medics or emergency medicine personnel. While extremity wounds are more amenable to compression to stop bleeding, 15% of Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) battle injuries are to the torso (chest, abdomen, pelvis and back), where compression cannot be applied. See Eastridge, B. (2009) Joint Theater Trauma Registry Data, September 2001-February 2008.
Non-compressible hemorrhage from truncal injury is the leading cause of potentially survivable deaths of American troops. See Kelly, J. F., Ritenour, A. E., McLaughlin D. F., Bagg, Apodaca, A. N., Mallak, C. T., Pearse, L., Lawnick, M. M., Champion, H. R., Wade, C. E., and Holcomb, J. B. (2008), Injury severity and causes of death from Operation Iraqi Freedom and Operation Enduring Freedom: 2003-2004 versus 2006. J Trauma 64, S21-26; discussion S26-27.
Patients who have penetrating wounds to the trunk are at risk of severe injuries to major vessels, causing massive hemorrhage, and are most likely to die during the acute (emergency) phase of care. Control of bleeding and limitation of blood loss is the only way to avoid the problems associated with massive hemorrhage in trauma.
Hemorrhagic shock is a severe and life-threatening condition. Over 21% of military casualties are in shock upon admission, and over 25% require a blood transfusion (Eastridge, B. (2009) Joint Theater Trauma Registry Data, June 2006-November 2009). Shock occurs when loss of blood leads to a lack of oxygen to the tissues, causing a systemic build-up of acids. In an attempt to reverse the acid build-up, the patient begins to hyperventilate and, along with other physiological changes, blood pressure increases and blood diverts from the renal system to the heart, lungs and brain. These symptoms occur due to the cellular response to the lack of oxygen, and lead to further breakdown and malfunction of cells, prompting various responses in the circulatory system.
If the problem is not treated or rectified, the cellular response will promote the dysfunction or complete failure of the vital organs, and the patient will die. Prevention of severe hemorrhage, or resuscitation with novel or advanced physiological resuscitation fluids, would diminish the onset of shock.
About 28% of patients with severe traumatic injury also have dysfunction in the process of coagulation (coagulopathy) when the patients arrive at the emergency department (MacLeod, J. B., Lynn, M., McKenney, M. G., Cohn, S. M., and Murtha, M. (2003), Early coagulopathy predicts mortality in trauma, J Trauma 55, 39-44). This dysfunction in the process of coagulation is often caused by dilution of the blood due to infusion of resuscitation products. Coagulopathy is associated with a 3.5- to 5-fold increase in mortality (MacLeod, J. B., Lynn, M., McKenney, M. G., Cohn, S. M., and Murtha, M. (2003), Early coagulopathy predicts mortality in trauma, J Trauma 55, 39-44); and Brohi, K., Cohen, M. J., and Davenport, R. A. (2007), Acute coagulopathy of trauma: mechanism, identification and effect, Curr Opin Crit Care 13, 680-685), and when combined with hypothermia and acidosis is known as the “lethal (or fatal) triad” because of the high likelihood of impending death.
Currently, there is no active intervention for non-compressible hemorrhage available to military or civilian medics and physicians; however, research of non-compressible hemorrhage control methods may offer solutions that could save lives.
Manufactured QuikClot® is an approved zeolite-based hemostatic agent for battlefield use. However, the exothermic reaction associated with QuikClot® as loose granules or as granules packaged in a mesh bag has potential burn effects at the site of application. Zeolites have hemostatic properties used to stop bleeding in severe hemorrhage. See Rhee P. Brown C, Martin M, Salim A. Plurad D, Green D, Chambers L, Demetriades D, Velmahos G, Alm H. (2008), QuikClot use in trauma for hemorrhage control: case series of 103 documented uses, J Trauma. 64(4):1093-9. See also, Arnaud F, Tomori T, Can W, McKeague A, Teranishi K, Prusaczyk K, McCarron R. (2008), Exothermic reaction in zeolite hemostatic dressings: QuikClot ACS and ACS+, Ann Biomed Eng. 36(10):1708-13.
It is widely accepted that severe bleeding is the leading cause of death from wounds on the battlefield, accounting for approximately over 50% of such deaths. It is estimated that one-third of these deaths could be prevented with enhanced hemorrhage control methods and devices. Such enhanced hemorrhage control would also prove very useful in non-military settings; e.g., hospitals and veterinary clinics, where hemorrhage is the second leading cause of death following trauma. No perfect solution currently exists for the effective treatment of excessive bleeding.
To date, application of continuous pressure with gauze bandage remains a primary intervention technique used to stem blood flow, especially flow from severely bleeding wounds. However, this continuous pressure with gauze bandage neither effectively nor safely stanches severe blood flow. This has been, and continues to be, a major survival problem in the case of severe life-threatening bleeding from a wound.
Furthermore, it is widely accepted that severe bleeding is the leading cause of death from wounds on the battlefield, accounting for approximately over 50 percent of such deaths. It is estimated that one-third of these deaths could be prevented with enhanced hemorrhage control methods and devices. Such enhanced hemorrhage control would also prove very useful in non-military settings; e.g., hospitals and veterinary clinics, where hemorrhage is the second leading cause of death following trauma.
Currently available hemostatic bandages such as collagen wound dressings or dry fibrin thrombin wound dressings are restricted to use in surgical applications, and are not sufficiently resistant to dissolution in high blood flow. These currently available hemostatic bandages also do not possess enough adhesive properties to serve any practical purpose. These currently available hemostatic bandages are also delicate and thus prone to failure should these hemostatic bandages be damaged by bending or loading with pressure. These hemostatic bandages are also susceptible to dissolution in hemorrhagic bleeding. Such dissolution and collapse of these hemostatic bandages can produce a loss of adhesion to the wound and allow bleeding to continue unabated.
It is generally accepted that hemostatic products for forward care in a battle zone must control bleeding quickly, be ready to use, be simple to apply, have a shelf life approaching two years, and prevent bacterial or viral transmission. The product's hemostatic action is time-critical in order to meet both military and civilian needs. Devices being investigated or used today as external methods of wound treatment range from absorbent pads containing clotting agents, pressure bandages, gauze, tourniquets for extremities, and trauma kits for wounds to the body.
A number of hemostatic products are available for treating wound trauma; for example, a bandage product using chitosan (deacetylated poly-N-acetyl glucosamine base, Hem Con Inc., Tigard, Oreg.), with limited shelf life and efficiency in stopping severe bleeding, Z-Medica Corporation, Wallingford, Conn., markets a pressure bandage product (QuikClot®) for use by U.S. troops. This product uses a granular, synthetic mineral zeolite to stop bleeding by adsorbing liquid and promoting clotting. However, QuikClot® generates heat that can cause burns if the bandage isn't applied correctly.
ActSys Medical Inc., Westlake Village, Calif., provides a hemostatic gauze product, ActCel®), which is a collagen-like natural substance created from chemically treated cellulose that expands 3-4 times its original size when in contact with blood, thus sealing off damaged vessels a d aiding clotting.
Medafor Inc., Minneapolis, Minn., sell a bio-inert, micro-porous polysaccharide macro-bead product that is synthesized from potatoes, called Trauma DEX®, which is a powdered micro-porous polymer product that stops bleeding by expanding at the wound site and dehydrating the blood, whereupon the body absorbs the material within 48 hours.
Another non-bandage approach employs a non-zeolite topical powder containing a hydrophilic polymer and potassium salt (Quick Relief, Sarasota, Fla.) which, after application, produces a flexible, protective scab to cover the wound site when the powder contacts the blood and slight pressure is applied.
No perfect solution currently exists for the effective treatment of excessive bleeding. Heat generation with respect to one type of agent is a major problem. The dressing's ability to adhere effectively when applied to deep wounds or wounds of irregular shape creates another major limitation. The ability to deal with excessive blood is another drawback, as is treatment and control of pressure bleeding from arterial bleeding.
Surgical and trauma wounds are the most common types of wounds addressed in the wound-care arena. Current bandages are made of gauze and are often applied in conjunction with an elastic bandage. The current bandages allow the wound to breath but are poor barriers to subsequent contamination. The current bandages cannot stop serious bleeding and require the application of pressure in the case of arterial bleeding. Conventional wound sealants fail to present an optimized combination of speed of clotting, effectiveness under pressure bleeding conditions, and clots that are dynamic over time in response to the needs of the trauma site. Typical wound sealants are usually used in conjunction with separate wound dressings. Clearly, surgical trauma caused by sharp objects occurs in a clean environment. However, trauma wounds not caused in a controlled environment are often intermediate sized, widespread, and dirty wounds with considerable tissue damage are found in road traffic accidents or on the battlefield.
Abrasions are generally caused by scraping of the skin's outer layer. Lacerations are jagged, irregular cuts or tears of the skin. Punctures are caused by an object piercing the skin layers, creating a small hole. Incisions are cuts commonly caused by knives or other sharp objects. Burns cause damage which may vary greatly in depth, size, and severity. Wounds due to firearms can be deep and with substantial tissue destruction. Dismemberment due to trauma requires immediate intervention to stop blood loss from the severed limb.
Liquid bandage formulations are available to the Over-the-Counter (OTC) consumer market. Liquid bandage preparations are often used for covering and protecting minor lacerations and abrasions, friction blisters and paper cuts. When applied to the skin, the solution in a liquid bandage evaporates to form a protective film over the application area and to promote healing. The polymerized film covering creates a moist wound healing environment to increase wound healing compared with conventional dressings. Most liquid bandage preparations claim to stop minor bleeding, create a protective seal over the wound, keep out water, dirt and germs, and generally act as a mechanical barrier to common microbial organisms and other forms of contamination. Liquid bandage produces are available from numerous commercial sources. Powder-based hemostats are also widely available OTC.
Cellulose products which are used include microcrystalline cellulose (Avicel range), methylcellulose, carboxymethyl cellulose, and other materials such as cross-linked polyvinyl pyrrolidone (PVP), used singly or in admixture. Also, suitable carriers include polyethylene glycol (PEG), in one embodiment having a molecular weight of about 1000; polyvinyl pyrrolidone (PVP), in one embodiment having an average molecular weight of about 50,000; Poly(acrylic acid), PVA, Poly (methyl vinyl ether co-maleic anhydride), Poly (ethylene oxide), and dextran, typically having an average molecular weight of about 40,000.
Shellfish derived chitosan was used in chitosan dressings. For example, U.S. Pat. No. 4,394,373 employs chitosan in liquid or powder form to agglutinate blood in microgram/mL quantities.
U.S. Pat. No. 4,452,785 is directed to a method of occluding blood vessels therapeutically by injecting chitosan directly into the vessels.
U.S. Pat. No. 4,532,134 relates to hemostasis, inhibiting fibroplasias, and promoting tissue regeneration by placing in contact with the tissue wound a chitosan solution or water-soluble chitosan. The chitosan forms a coagulum, which prevents bleeding.
U.S. Pat. No. 5,700,476 describes collagen based structurally inhomogeneous sponges for wound dressings and/or implant applications formed by freeze drying techniques employing at least one pharmacological agent and at least one substructure.
U.S. Pat. No. 2,610,625 relates to freeze dried sponge structures that are highly effective in stopping the flow of blood or other fluids and which will be absorbed after a time in the body.
U.S. Pat. No. 5,858,350, relates to a process to make diatom derived biomedical grade, high purity chitin and chitin derivatives.